Lipedema is an estrogen-dependent disorder and estrogen directly activates mast cells (white blood cells associated with allergies and inflammation) and enhances histamine release. Histamine in turn can play a role in lymphatic dysfunction and vascular permeability changes.
While direct evidence linking histamine specifically to lipedema pathophysiology remains limited in available research data, the estrogen-mast cell-histamine-lymphatic axis provides a plausible mechanistic framework for understanding an aspect of this complex disorder.
Are Mast Cells “Activated” or in Higher Quantity in Lipedema
This is largely not well-quantified in lipedema, but mast cells do tend to accumulate in adipose tissue and release inflammatory cytokines like tryptase, chymase, and TGF-β that are involved in driving fibrosis.[1,2]
How Histamine Affects the Lymphatic System
Histamine increases lymphatic endothelial permeability (leakier lymphatics) and changes lymphatic contractility (less pumping) which can lead to more edema.[3]
The Hormone Factor
If you’re perimenopausal, perhaps you sometimes experience seemingly bizarre symptoms like random itching or worsening allergies. Evidence shows that fluctuating estrogen levels in perimenopause may trigger mast cell degranulation and surges in histamine. This can also happen during the menstrual cycle as estrogen levels fluctuate.[4,5] In post-menopausal women there is evidence that the estrogen deficiency results in mast cell-mediated tissue remodeling. This remodeling increases fibrosis in the heart and other organs,[6,7] suggesting it could be a driver in worsening fibrosis in lipedema.
Does this mean lipedema patients have MCAS (Mast Cell Activation Syndrome)?
This connection with histamine and mast cell activation does not mean that all patients with lipedema have MCAS. MCAS is a separate disorder with its own constellation of symptoms, its own specific diagnostic criteria, and a different inflammatory profile than lipedema.[8] If someone has MCAS and lipedema, it’s possible that the combined conditions may result in even higher histamine levels, but there are no studies to date that shows that MCAS is present in higher levels in patients with lipedema.[9] This may represent more of a gap in research and understanding as we do see higher levels of hypermobility disorders like Ehlers-Danlos Syndrome in lipedema and these conditions often do co-occur with MCAS and dysautonomia.[10] Hopefully future studies will further evaluate this possible connection.
Could antihistamines be beneficial in lipedema?
There are several plausible mechanisms for antihistamines to be beneficial in lipedema including effects on vascular permeability, anti-edema, and anti-inflammatory effects, however no direct studies have been conducted to date on this topic.
Limitations on this approach and theory are that we do have evidence of lipedema having a different M2 macrophage predominant profile that differs from a classic allergic inflammatory profile and would not explain some of the other characteristics of lipedema.[11]
This post was updated 8/6/2026
Sources
- Elieh Ali Komi D, Shafaghat F, Christian M. Crosstalk between mast cells and adipocytes in physiologic and pathologic conditions. Clin Rev Allergy Immunol. 2020;58(3):388-400.
- Żelechowska P, Agier J, Kozłowska E, Brzezińska-Błaszczyk E. Mast cells participate in chronic low-grade inflammation within adipose tissue. Obes Rev. 2018;19(5):686-696.
- Plaku KJ, von der Weid PY. Mast cell degranulation alters lymphatic contractile activity through action of histamine. Microcirculation. 2006;13(3):219-227.
- Jonassen F, Granerus G, Wetterqvist H. Histamine metabolism and female sex hormones in women. Acta Obstet Gynecol Scand. 1976;55(4):297-304.
- Jonassen F, Granerus G, Wetterqvist H. Histamine metabolism during the menstrual cycle. Acta Obstet Gynecol Scand. 1976;55(4):305-310.
- Maslov PZ, Kim JK, Argulian E, et al. Is cardiac diastolic dysfunction a part of post-menopausal syndrome? JACC Heart Fail. 2019;7(3):192-203.
- Garate-Carrillo A, Gonzalez J, Ceballos G, Ramirez-Sanchez I, Villarreal F. Sex related differences in the pathogenesis of organ fibrosis. Transl Res. 2020;222:41-55.
- Weiler CR, Austen KF, Akin C, et al. AAAAI Mast Cell Disorders Committee Work Group report: Mast cell activation syndrome (MCAS) diagnosis and management. J Allergy Clin Immunol. 2019;144(4):883-896.
- Afrin LB, Butterfield JH, Raithel M, Molderings GJ. Often seen, rarely recognized: mast cell activation disease–a guide to diagnosis and therapeutic options. Ann Med. 2016;48(3):190-201.
- Theoharides TC, Kempuraj D, Maitland A. Mast cell activation disorders: mechanisms, comorbidities and look-alike. Expert Rev Clin Immunol. 2026;22(2):185-199.
- Wolf S, Rannikko JH, Virtakoivu R, et al. A distinct M2 macrophage infiltrate and transcriptomic profile decisively influence adipocyte differentiation in lipedema. Front Immunol. 2023;14:1158978.
